Copper(II) tetraphenylporphine (CuTPP) has been found to partition favorably into dimyristoylphosphatidylcholine (DMPC) bilayer membrane. Electron paramagnetic resonance (EPR) spectra of oriented liquid-crystalline DMPC membranes indicate that for a high (about 1/25) CuTPP/DMPC molar ratio, CuTPP is oriented with the plane of the molecule parallel to the bilayer surface. This result is in clear contrast to our previous observation that at low (less than or equal to 1/100) CuTPP/DMPC molar ratio, the plane of the molecule is preferentially perpendicular to the membrane surface (M. Pasenkiewicz-Gierula, W. K. Subczynski, and W. E. Antholine (1997) J. Phys. Chem. 101, 5596-5606). Measurements of the collision rate between CuTPP and the nitroxide moiety of stearic acid spin labels located at different depths in the membrane using saturation-recovery EPR spectroscopy lead to the conclusion that the change of the CuTPP orientation at a high CuTPP/DMPC molar ratio is coupled with self-association (crystallization) of CuTPP molecules near the lipid bilayer center. Additional confirmation of this conclusion comes from comparison of EPR spectra of CuTPP in liquid-crystalline DMPC membranes with those of CuTPP crystals and aggregates. The self-association process depends both on the CuTPP/DMPC molar ratio and the time after sample preparation.